Oral Tongue Squamous Cell Carcinoma Research Articles

The maximum standardized uptake value increment calculated by dual-time-point 18F-fluorodeoxyglucose positron emission tomography predicts survival in patients with oral tongue squamous cell carcinoma.

ABSTRACTThe aim of this study was to investigate the prognostic value of dual-time-point (DTP) 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging in primary oral tongue squamous cell carcinoma (OTSCC). The study included 52 patients who underwent preoperative 18F-FDG PET scans at two time points, namely 1 h and 2 h after injection. The following PET parameters were calculated: maximum standardized uptake value (SUVmax) for both time points (SUV early, SUV delayed); retention index (RI); and SUVmax increment (ΔSUVmax). Receiver operating characteristic (ROC) curve analysis was performed to define the optimal cutoff point for these parameters. Overall survival was calculated using the Kaplan–Meier method. Prognostic factors for patients with OTSCC were evaluated using the univariate log-rank test and a multivariate Cox proportional hazards model. ROC analysis revealed that the area under the curve was higher and more accurate for ΔSUVmax than for the other parameters. Additionally, patients with a ΔSUVmax ≥0.9 had significantly worse survival outcomes (28.9% vs 92.6%; p < 0.01). Univariate analysis showed that prognosis was significantly correlated with clinical T stage, local recurrence, perineural invasion, vascular invasion, and PET parameters (p < 0.05 for all). Multivariate analysis showed that local recurrence (hazard ratio = 3.60; p = 0.02) and ΔSUVmax (hazard ratio = 8.43; p < 0.01) were independent prognostic factors. ΔSUVmax determined using DTP 18F-FDG PET may be an additional prognostic factor in OTSCC patients.

CXC chemokine‑7 inhibits growth and migration of oral tongue squamous cell carcinoma cells, mediated by the epithelial‑mesenchymal transition signaling pathway.

Oral tongue squamous cell carcinoma (OTSCC) is the most common oral malignancy with different histopathological symptoms and etiology of tumorigenesis. Migration and invasion is the most important characteristics of OTSCC, and limits tumor therapy in clinics. The epithelial‑to‑mesenchymal transition (EMT) signaling pathway is an important process in the progress of tumor cell migration and invasion. Previous studies have indicated that C‑X‑C chemokine receptor‑7 (CXCR‑7) promotes the progression and metastasis of tumor cells, presenting a potential target molecule for cancer therapy. The present study investigated the inhibitory effects of C‑X‑C chemokine‑7 (CXC‑7) on human OTSCC cells both in vitro and in vivo. The results demonstrated that the Tca8113 human OTSCC cell line expressed higher levels of CXC‑7 mRNA compared with the hNOE human normal oral epithelial cell line. MTT assays indicated that CXC‑7 suppressed Tca8113 cell growth, and the cytotoxicity of CXC‑7 was indicated as the cell survival of the negative control group was significantly decreased compared with the blank control and hNOE cells. Migration and invasion assays revealed that CXC‑7 inhibited Tca8113 cell local expansion and distant metastasis. In addition, the results demonstrated that the extracellular signal‑regulated kinase (ERK)/protein kinase B (AKT) signaling pathway was inhibited after CXC‑7 treatment in Tca8113 cells. N‑cadherin, E‑Cadherin, Snail and Slug expression levels in the ERK/AKT signaling pathway were inhibited in Tca8113 cells after treatment with CXC‑7. It was demonstrated that important extracellular matrix proteins involved in cell migration, including Slug, collagen type I and Vimentin, were significantly downregulated by CXC‑7 treatment. In conclusion, CXC‑7 inhibited growth and migration in OTSCC cells, mediated by the EMT signaling pathway. This suggests that CXC‑7 serves an inhibitory role in OTSCC migration, implicating CXCR‑7 as a promising biomarker for chemokine receptor‑based drug development.

Establishment and characterization of an oral tongue squamous cell carcinoma cell line from a never-smoking patient

ObjectiveThe rising incidence of oral tongue squamous cell carcinoma (OTSCC) in patients who have never smoked and the paucity of knowledge of its biological behavior prompted us to develop a new cell line originating from a never-smoker. Materials and methodsFresh tumor tissue of keratinizing OTSCC was collected from a 44-year-old woman who had never smoked. Serum-free media with a low calcium concentration were used in cell culture, and a multifaceted approach was taken to verify and characterize the cell line, designated UCSF-OT-1109. ResultsUCSF-OT-1109 was authenticated by STR DNA fingerprint analysis, presence of an epithelial marker EpCAM, absence of human papilloma virus (HPV) DNA, and SCC-specific microscopic appearance. Sphere-forming assays supported its tumorigenic potential. Spectral karyotype (SKY) analysis revealed numerical and structural chromosomal abnormalities. Whole-exome sequencing (WES) identified 46 non-synonymous and 13 synonymous somatic single-nucleotide polymorphisms (SNPs) and one frameshift deletion in the coding regions. Specifically, mutations of CDKN2A, TP53, SPTBN5, NOTCH2, and FAM136A were found in the databases. Copy number aberration (CNA) analysis revealed that the cell line loses chromosome 3p and 9p, but lacks amplification of 3q and 11q (as does HPV-negative, smoking-unrelated OTSCC). It also exhibits four distinctive focal amplifications in chromosome 19p, containing 131 genes without SNPs. Particularly, 52 genes showed >3- to 4-fold amplification and could be potential oncogenic drivers. ConclusionWe have successfully established a novel OTSCC cell line from a never-smoking patient. UCSF-OT-1109 is potentially a robust experimental model of OTSCC in never-smokers.

Predictive Significance of Tumor Depth and Budding for Late Lymph Node Metastases in Patients with Clinical N0 Early Oral Tongue Carcinoma.

In clinical N0 early oral tongue carcinoma, treatment of occult lymph node metastasis is controversial. The purpose of this study was to assess the histopathological risk factors for predicting late lymph node metastasis in early oral tongue carcinoma. We retrospectively reviewed 48 patients with early oral tongue squamous cell carcinoma. Associations between the histopathological factors (depth of tumor, differentiation, blood vessel invasion, lymphatic invasion, and tumor budding) and late lymph metastasis were analyzed. Although the univariate analysis identified blood vessel invasion, lymphatic invasion, and high-grade tumor budding as predictive factors for neck recurrence (p < 0.001), the Cox proportional hazards model identified high-grade tumor budding as an independent predictive factor (p < 0.01). The combination of a tumor depth ≥ 3mm and high-grade tumor budding yielded high diagnostic accuracy. Tumor depth and budding grade were identified as histopathological risk factors for late neck recurrence in clinical N0 early oral tongue carcinoma.

The Prevalence of Human Papilloma Virus in Squamous Cell Carcinoma of Oral Tongue

Oral tongue Squamous Cell carcinoma (SCC) commonly involves males between the sixth to eighth decades of life. Major risk factors are tobacco usage and alcohol consumption. The increasing number of patients developing oral tongue cancer without these well-known risk factors suggests that a viral infection, such as Human Papillomavirus (HPV), may be responsible for this increase, by acting as an oncogenic agent. This study investigated the prevalence of HPV infection and its clinicopathologic significance in oral tongue SCCs. Tissue blocks from a total of 50 cases (patients with oral tongue SCC) and 50 controls (palatine tonsillar tissues with benign diagnosis) were selected. DNA was extracted from tumoral and non-tumoral tissue blocks. Detection of common HPV DNA by nested Polymerase Chain Reaction (PCR), and high-risk genotypes, HPV 16 and HPV 18, by conventional PCR, was achieved and the results correlated with clinicopathological parameters. Of the 50 patients (18 males and 32 females with a mean age of 57.36±12.18 years, and age range of 27 to 86 years), 7 (14%) had HPV positive results. None of the control group subjects had HPV DNA positive results (P-value of 0.012). The HPV genotype 16/18 was not detected in positive cases. No statistically significant association was found between HPV status and gender, age, tumor grade, tumor stage or lymph node involvement. Although there was a significantly higher prevalence of HPV in oral tongue SCC, its association with carcinogenesis in this area requires further studies.

What additional treatment is indicated for oral cavity cancer with isolated perineural invasion?

What additional treatment is indicated for oral cavity cancer with isolated perineural invasion?

MiR-15b inhibits cancer-initiating cell phenotypes and chemoresistance of cisplatin by targeting TRIM14 in oral tongue squamous cell cancer.

Oral tongue squamous cell carcinoma (TSCC) is one of the most lethal cancers within the oral cavity and its prognosis remains dismal due to the paucity of effective therapeutic targets. The formation of cancer-initiating cells (CICs) and epithelial-mesenchymal transition (EMT) are pivotal events involved in the dismal prognosis. They have been shown to be related to the resistance to cisplatin treatment. In the present study, we showed that TRIM14 induced formation of cancer-initiating cells and EMT in TSCC SCC25 cells. Its overexpression promoted cisplatin resistance in the SCC25 cells. We found that overexpression of miR-15b suppressed TRIM14 and inhibited CIC phenotypes in the SCC25 cells. Moreover, overexpression of miR-15b promoted mesenchymal-epithelial transition (MET) in the SCC25 cells and sensitized cisplatin-resistant SCC25 (SCC25-res) cells to cisplatin. Thus, we conclude that miR-15b inhibited cancer stem cell phenotypes and its restoration reversed the chemoresistance of cisplatin by targeting TRIM14 in TSCC. Elucidating the molecular mechanism of EMT and cancer stem cells in TSCC may further aid in the understanding of the pathogenesis and progression of the disease, and offer novel targets for the discovery of new drugs.

CD163-Positive Macrophages Within the Tumor Stroma Are Associated With Lymphangiogenesis and Lymph Node Metastasis in Oral Squamous Cell Carcinoma

Increasing evidence shows that tumor stromal components, particularly tumor-associated macrophages (TAMs), play an important role in the tumor progression of various solid malignant tumor types. However, their roles in oral squamous cell carcinoma (OSCC) have not been fully elucidated. Seventy human tongue OSCC samples were analyzed in the present study. Immunohistochemistry was used to investigate the correlations between the densities of CD68-, CD163-, and CD204-positive TAMs and clinicopathologic parameters. Lymphatic vessel density (LVD) was estimated using the D2-40 antibody. Invitro studies also were conducted to investigate the effect of conditioned medium (CM) derived from OSCC cell lines on cytokine and chemokine expression in RAW264.7 mouse monocytic leukemia cells. Increased densities of CD68-, CD163-, and CD204-positive TAMs were significantly correlated with lymph node metastasis (P=.035, .0082, and .038, respectively). Higher LVD occurred considerably more frequently in patients with nodal metastasis than in those without such metastasis. Moreover, LVD was considerably increased in patients with higher CD163-positive TAM densities. Studies using immunofluorescence showed that vascular endothelial growth factor (VEGF)-C was expressed in 52 of 70 patients with CD163-positive TAMs (74.2%). Moreover, CM derived from OSCC cell lines stimulated the expression of Il-10, Ccl22, Vegf-a, and Vegf-c in RAW264.7cells; however, Il-12p35 expression levels were not changed. CD163-positive TAMs promote lymphangiogenesis through VEGF-C expression, which contributes to regional lymph node metastasis in OSCC.

Stromal interaction molecule 1 regulates growth, cell cycle, and apoptosis of human tongue squamous carcinoma cells.

Oral tongue squamous cell carcinoma (OTSCC) is the most common type of oral carcinomas. However, the molecular mechanism by which OTSCC developed is not fully identified. Stromal interaction molecule 1 (STIM1) is a transmembrane protein, mainly located in the endoplasmic reticulum (ER). STIM1 is involved in several types of cancers. Here, we report that STIM1 contributes to the development of human OTSCC. We knocked down STIM1 in OTSCC cell line Tca-8113 with lentivirus-mediated shRNA and found that STIM1 knockdown repressed the proliferation of Tca-8113 cells. In addition, we also showed that STIM1 deficiency reduced colony number of Tca-8113 cells. Knockdown of STIM1 repressed cells to enter M phase of cell cycle and induced cellular apoptosis. Furthermore, we performed microarray and bioinformatics analysis and found that STIM1 was associated with p53 and MAPK pathways, which may contribute to the effects of STIM1 on cell growth, cell cycle, and apoptosis. Finally, we confirmed that STIM1 controlled the expression of MDM2, cyclin-dependent kinase 4 (CDK4), and growth arrest and DNA damage inducible α (GADD45A) in OTSCC cells. In conclusion, we provide evidence that STIM1 contributes to the development of OTSCC partially through regulating p53 and MAPK pathways to promote cell cycle and survival.

Regional recurrence in early stage I–II oral tongue cancer: a single institutional study and review of the literature

Conclusions: There is a high propensity for locoregional and isolated regional failure in stage II patients, even though treated with combined therapy. In stage I patients the risk of isolated regional failure was moderate, at levels below 10%.Background: The neck treatment of early stages of oral tongue squamous cell carcinoma (OTSCC) are still debatable, considering that previous studies have produced diverting results. The purpose of this study is to report on the outcome of patients with stages I–II, with special respect to regional outcome.Materials and methods: All patients treated for OTSCC at Karolinska University Hospital between 2008–2014 were included. Patient demographics, intention of treatment, treatment modality, time of follow-up and status at follow-up, recurrence, and place of recurrence were recorded.Results: Of 230 patients, 149 presented within stages I and II. Of those, 105 were electively treated to the neck. In stage I, the risk of presence of disease in the neck specimen was four out of 63 (6%), whereas 17 out of 41 (41%) were positive in stage II patients. The overall risk of isolated regional failure at any time in stage I patients was six out of 89 and in stage II 25 out of 60.

Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for T2-4N0 tongue cancer: control of occult neck metastasis

To evaluate the therapeutic results and control of occult neck metastasis in patients with T2-4N0 oral tongue squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy. Forty-two patients with T2-4N0 tongue cancer (17 with late T2; 13 with T3; and 12 with T4a disease, M0) were treated with intra-arterial chemoradiotherapy. Treatment consisted of retrograde superselective intra-arterial chemotherapy (docetaxel 50-70mg/m2, cisplatin 125-175mg/m2) and daily concurrent radiotherapy (50-70Gy) for 5-7weeks. The median follow-up for all patients was 46.5months (range, 8-105months). Primary-site complete response was achieved in 42 of 42 cases (100%). Three-year overall survival, progression-free survival, and local control rates were 85.0%, 77.8%, and 91.7%, respectively. Delayed neck metastasis was detected in 5 of 42 cases (11.9%). Grade 3 or 4 toxic changes included oral mucositis in 92.9%, neutropenia in 21.4%, and thrombocytopenia in 4.8%. Grade 3 toxicities included anemia in 16.7%, radiation dermatitis in 9.5%, nausea in 4.8%, and fever in 2.4%. Retrograde superselective intra-arterial chemotherapy for T2-4N0 tongue cancer provided good overall survival and local control rates and was effective for occult neck metastasis.

Elective neck dissection in unilateral carcinomas of the tongue: Unilateral versus bilateral approach

PurposeElective neck dissection (END) is a common primary treatment strategy for oral tongue squamous cell carcinoma (OTSCC), although uncertainty remains regarding the necessary extent of END for strictly unilateral early stage OTSCC. The authors evaluated two END variations, unilateral and bilateral, to determine the optimal extent. Materials and methodsA retrospective cohort study was performed on patient data from two departments of oral and maxillofacial surgery. All previously untreated patients from both clinics who were diagnosed with early-stage (pT1-2) unilateral OTSCC were included. The following variables were collected: age, gender, END type/extent, tumor localization, later nodal metastasis, and TNM status. Statistical analyses were performed (p < 0.05). ResultsA total of 150 patients were identified, 105 receiving unilateral END and 45 bilateral END. The rates of postoperative positive lymph nodes were 21.9% for ipsilateral END and 26.7% for bilateral END (bilateral END: all positive nodes ipsilateral). In all, 14 patients in the ipsilateral group developed nodal metastasis during tumor aftercare (11 patients ipsilateral, 3 patients contralateral neck). In the bilateral group, nodal metastasis was later observed in 4 cases (8.9%; 3 cases ipsilateral, 1 case contralateral neck). Statistical analysis could not detect significant differences between the END procedures. ConclusionAs both procedures lead to similar results in preventing or omitting possible later nodal metastasis, the two methods seem to be valuable alternatives. In conclusion, we recommend bilateral END because of advantages with regard to oncologic safety and esthetic outcome, but the decision for END should always be according to the patient's general health status, comorbidities, and individual tumor risk profile.

DNA base excision repair proteins APE-1 and XRCC-1 are overexpressed in oral tongue squamous cell carcinoma.

DNA repair systems play a critical role in protecting the human genome from damage caused by carcinogens. Modifications in DNA repair genes may be responsible for tumor development and resistance of malignant cells to chemotherapeutic agents. The major pathway for oxidative DNA damage repair is the base excision repair pathway. This study aimed to assess the immunoexpression of DNA repair proteins APE-1 and XRCC-1 and its association with clinical, histologic, and survival parameters in oral tongue squamous cell carcinoma, to investigate a possible role for those proteins in tumor behavior. The expression of APE-1 and XRCC-1 was evaluated by immunohistochemistry in 82 cases of oral tongue squamous cell carcinoma. Histopathological grading was performed for each case. Pearson's chi-square and Fisher's exact tests were used to determine the association between protein expressions and clinicopathological features of tumors, whereas Kaplan-Meier curves and Cox regression were used to analyze disease-specific and disease-free survival. Statistical significance was set at P ≤ 0.05. APE-1 was highly expressed in the nucleus and cytoplasm in 64.6% of cases, and XRCC-1 showed overexpression only in the nucleus in 61% of cases. High expression of XRCC-1 was significantly associated with tumors at early clinical stages (I and II, P < 0.01) and nodal status (P = 0.03). Both proteins were not associated with other clinical parameters, histopathological grading, or survival. DNA base excision repair proteins APE-1 and XRCC-1 are upregulated in oral tongue squamous cell carcinoma, and XRCC-1 expression is associated with better clinical staging and nodal status.

Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups

Background:Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer.Methods:Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies.Results:Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively.Conclusions:Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.

MiR-486-3p, miR-139-5p, and miR-21 as Biomarkers for the Detection of Oral Tongue Squamous Cell Carcinoma.

Oral tongue squamous cell carcinoma (TSCC) is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. The aims of the present study were to test the feasibility of performing the microRNA profiling analysis on archived TSCC specimens and to assess the potential diagnostic utility of the identified microRNA biomarkers for the detection of TSCC. TaqMan array-based microRNA profiling analysis was performed on 10 archived TSCC samples and their matching normal tissues. A panel of 12 differentially expressed microRNAs was identified. Eight of these differentially expressed microRNAs were validated in an independent sample set. A random forest (RF) classification model was built with miR-486-3p, miR-139-5p, and miR-21, and it was able to detect TSCC with a sensitivity of 100% and a specificity of 86.7% (overall error rate = 6.7%). As such, this study demonstrated the utility of the archived clinical specimens for microRNA biomarker discovery. The feasibility of using microRNA biomarkers (miR-486-3p, miR-139-5p, and miR-21) for the detection of TSCC was confirmed.

PTK7 is a molecular marker for metastasis, TNM stage, and prognosis in oral tongue squamous cell carcinoma.

The prognosis of oral tongue squamous cell carcinoma (OTSCC) is poor, and it would be beneficial to identify prognostic markers for optimization of treatment. Protein tyrosine kinase 7 (PTK7) is a receptor tyrosine kinase that is aberrantly expressed in human cancers. No exploration of the role of PTK7 in OTSCC has been reported. We detected expression of PTK7 protein in a set of tissue samples of OTSCC. The relationship between PTK7 expression and clinicopathologic parameters and overall survival of patients was analyzed. The expression level of PTK7 protein in OTSCC was increased relative to that in normal squamous cells. High expression of PTK7 was positively associated with TNM stage (p = 0.024), tumor differentiation (p = 0.019), and lymph node metastasis (p = 0.077). Patients with high expression of PTK7 had poor overall survival (p = 0.058). Our data indicate that PTK7 protein expression is associated with the prognosis of OTSCC and may serve as a therapeutic target.

MiR-486-3p, miR-139-5p, and miR-21 as Biomarkers for the Detection of Oral Tongue Squamous Cell Carcinoma.

Oral tongue squamous cell carcinoma (TSCC) is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. The aims of the present study were to test the feasibility of performing the microRNA profiling analysis on archived TSCC specimens and to assess the potential diagnostic utility of the identified microRNA biomarkers for the detection of TSCC. TaqMan array-based microRNA profiling analysis was performed on 10 archived TSCC samples and their matching normal tissues. A panel of 12 differentially expressed microRNAs was identified. Eight of these differentially expressed microRNAs were validated in an independent sample set. A random forest (RF) classification model was built with miR-486-3p, miR-139-5p, and miR-21, and it was able to detect TSCC with a sensitivity of 100% and a specificity of 86.7% (overall error rate = 6.7%). As such, this study demonstrated the utility of the archived clinical specimens for microRNA biomarker discovery. The feasibility of using microRNA biomarkers (miR-486-3p, miR-139-5p, and miR-21) for the detection of TSCC was confirmed.

Incidence of occult metastasis in clinically N0 oral tongue squamous cell carcinoma and its association with tumor staging, thickness, and differentiation

Introduction: Oral squamous cell carcinoma (SCC) is the most frequent head and neck cancer. The metastatic dissemination of these tumours usually occurs through the lymphatic system. The presence of occult lymph node metastasis is the most important prognostic factor. The high incidence of occult lymph nodal metastasis is a strong argument for the indication of elective neck dissection. However, there is a high percentage of patients who do not have metastasis in the pathological exam (pN0). Taking a homogenous group of patients all of whom received primary surgical treatment, at the same institution without prior radiotherapy or chemotherapy, applying stringent patient selection criteria, and standard pathological evaluation methods across the group, this study aims to establish predictors of cervical node metastasis in squamous carcinomas of the oral tongue. Result: During the study period, a total of 112 patients (98 males and 14 females; Mean age 49.7 years (range 15-70)) underwent resection of the primary tumor with SOND for N0 lymph node status of neck. A total of 1489 lymph nodes were analyzed in this study. Occult metastasis was found in 26 patients (23.2%). T-stage 4 was found to be a statistically significant predictor of occult lymph node metastasis in a cN0 neck. (95% CI, p-value 0.02). There was no correlation between gender, tumor thickness, and tumor differentiation and occurrence of occult metastasis. Discussion: Controversy exists over management of the neck in patients with cN0 oral SCC. As is evident there is no consistent statistically significant factor that can be attributed as a predictor of occult metastasis in head and neck cancer of the oral cavity. The search to identify reliable and accurate predictor(s) of occult metastases, or approaches to the management of patients with cN0 oral SCC, must continue. In absence of such predictors, keeping the high incidence of occult metastasis in mind, we recommend END in all cases of N0 OSCC.

Inhibition of mTOR/eIF4E by anti-viral drug ribavirin effectively enhances the effects of paclitaxel in oral tongue squamous cell carcinoma

Upregulation of eIF4E is associated with poor clinical outcome in many human cancers and represents a potential therapeutic target. However, the function of eIF4E remains unknown in oral tongue squamous cell carcinoma (OTSCC). In this work, we show that ribavirin, an anti-viral drug, effectively augments sensitivity of OTSCC cells to paclitaxel via inhibiting mTOR/eIF4E signaling pathway. Ribavirin dose-dependently inhibits proliferation and induces apoptosis in SCC-9 and CAL27 cells. Combination of ribavirin and paclitaxel are more effective in inhibiting proliferation and inducing apoptosis in OTSCC cells. Importantly, the in vivo efficacy of ribavirin and its synergism with paclitaxel is confirmed by two independent OTSCC xenograft mouse models. Mechanistically, ribavirin significantly decreases mTOR/eIF4E signaling pathway in OTSCC cells via suppressing phosphorylation of Akt, mTOR, 4EBP1 and eIF4E. Overexpression of the phosphor-mimetic form of eIF4E (eIF4E S209D) but not the nonphosphorylatable form (eIF4E S209A) reverses the effects of ribavirin, confirming that eIF4E inhibition is the mechanism of action of ribavirin in OTSCC cells. In addition, eIF4E depletion significantly enhances the anti-proliferative and pro-apoptotic effects of paclitaxel, demonstrating the critical role of eIF4E in OTSCC cell response to paclitaxel. Our work is the first to demonstrate the efficacy of ribavirin as a single agent and synergism as combination with paclitaxel in OTSCC in vitro and in vivo. Our findings also demonstrate the therapeutic value of inhibiting eIF4E in OTSCC treatment.

Retrospective observational study of occult cervical lymph-node metastasis in T1N0 tongue cancer.

Delayed neck metastasis is the most significant prognostic factor for early tongue cancer. The main strategies for controlling cervical lymph nodes in Japan are elective neck dissection or watchful waiting. Elective neck dissection offers significantly better survival, but adversely impacts patient quality of life; consequently, here we investigated how to identify high-risk patients warranting elective neck dissection. We retrospectively evaluated 67 patients with T1N0 oral tongue squamous cell carcinoma who underwent primary treatment in our department from April 2001 to March 2015. All the patients underwent watchful waiting alone for neck management. We investigated the rates of occult neck metastasis, prognosis and circumstances of recurrence, and associations with pathological tumor thickness, depth and muscle invasion by the primary tumor. Correlation between the thickness in pathological specimens and that at magnetic resonance imaging was additionally investigated. Neck recurrence was evident in 20 patients, of which 19 developed within 1 year. Therefore, the rate of occult neck metastasis was 29.9%. Patients with muscle invasion, tumor thickness ≥2 mm or tumor depth ≥2 mm on surgical specimens were significantly more likely to develop delayed neck metastasis. Prognosis was significantly worse for patients with muscle invasion or tumor thickness ≥2 mm. Thickness using magnetic resonance imaging was well correlated with pathological thickness. Patients with tumors ≥2 mm in thickness or muscle invasion developed neck metastasis, suggesting that elective neck dissection may be warranted for patients with these findings. For preoperative assessment of the need for elective neck dissection, magnetic resonance imaging would be a potential modality for T1N0 tongue cancer.